Kromakalim is an anti-hypertensive composition of novel acting mechanism. It belongs to the peripheral group of anti-hypertensive agents, it acts by opening the potassium channels in the smooth muscle cells and it thereby prevents the accumulation of electric potential through the membranes. Accordingly it belongs to the potassium channel activators [Drugs of the Future II, 175 (1986), 12, 284 (1987), 13, 269 (1988), 14, 276 (1989)].
Several independent methods are known for the preparation of Kromakalim and analogues thereof: J. M. Evans et al.: J. Med. Chem. 26, 1582 (1983), J. M. Evans et al.: J. Med. Chem. 27, 1127 (1984), V. A. Ashwood et al.:J. Med. Chem. 29, 2194 (1986), EPO 0 009 912, EPO 0 046 652, EPO 0 076 075, EPO 0 093 535, EPO 0 120 426, EPO 0 120 427, EPO 0 120 428, EPO 0 126 311, EPO 0 126 350, EPO 0 126 367, EPO 0 138 134, EPO 0 173 848, EPO 0 271 271, EPO 0 274 821, EPO 0 277 611, EPO 0 286 975, PCT WO 85 00602, PCT WO 85 01290, PCT WO 88 00822.
According to EPO 0 076 075 describing the possibilities for preparing Kromakalim 4-cyano-phenol of the formula (I) ##STR4## is reacted with 3-chloro-3-methyl-butyne resulting in propargyl-ether of the formula (IX) ##STR5## which is then subjected to ring closure to produce 6-cyano-2,2-dimethyl-2H-1-benzopyran of the formula (III) ##STR6## The compound of the formula (III) is then converted through 6-cyano-trans-3-bromo-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-ol to 6-cyano-3,4-dihydro-3,4-epoxy-2,2-dimethyl-2H-1-benzopyran of the formula (V). ##STR7## From the compound of the formula (V) the end-product of the formula (VI) can be obtained by three independent routes.
1. The compound of the Formula (V) is reacted with ammonia to produce 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-amino-2H-1-benzopyran-3-ol of the formula (VII) ##STR8## which is then reacted with 4-chloro-butyric acid chloride to produce a compound of the formula (VIII) ##STR9## and this is then subjected to ring closure in a sodium-hydride-tetrahydrofuran system.
2. The compound of the formula (V) is reacted with 4-amino-butyric acid in a sodium-hydrogen-carbonate-ethanol system, and the ring closure results in the end-product of the formula (VI).
3. The compound of the formula (V) is reacted with 2-pyrrolidone in the presence of sodium hydride and dimethylsulfoxide and the end-product of the formula (VI) is obtained.
When reproducing the working examples of EPO 0 076 075 we observed the following circumstances:
4-cyano-phenol reacts with 3-chloro-3-methyl-butyne in the presence of sodium hydroxide-benzyl-trimethyl-ammonium-hydroxide-water and dichloro-butane at room temperature within 5-6 days, according to the patent specification propargyl-ether of the formula (IX) can be obtained with a yield of 69%. The reaction was repeated several times but only a 46-50% yield could be achieved. The reaction was carried out in acetone, dimethyl-sulfoxide, N,N-dimethyl-formamide solvent in the presence of potassium-carbonate and potassium-iodide at 50.degree.-150.degree. C., and after 30-40 hours reaction only 40-55% yield could be achieved. The further problem is that only 3-hydroxy-3-methyl-butyne is commercially available and according to our experiences 3-chloro-3-methyl-butyne can be prepared from this compound with a yield of only 55-60% by a difficult reaction. 3-chloro-3-methyl-butyne is a compound of poor stability; it decomposes upon standing and at the same time it polymerizes during the alkylation reaction or it decomposes at higher temperature. It can be said that the reaction of 4-cyano-phenol of the formula (I) and 3-chloro-3-methyl-butyne results in propargyl-ether of the formula (IX) with a yield of only 45-55%, and this is then subjected to ring-closure in ortho-dichloro-benzene to 6-cyano-2,2-dimethyl-2H-1-benzopyran of the formula (III) with a yield of 80% according to EPO 0 076 075. According to our own experimental experience the reaction can be carried out with a yield of at most 70% and the purification of the product of the formula (III) is a complicated procedure and can be performed by vacuum distillation or column chromatography. By this reaction the chromene derivatives of the formula (III) can be obtained with a yield of 35% related to 4-cyano-phenol of the formula (I) and with a yield of 23% related to 3-chloro-3-methyl-butyne.
3-bromo-4-hydroxy-derivatives of the formula (IV) ##STR10## could be prepared from the chromene of the formula (III) in a system of dimethyl-sulfoxide and water with a yield of 90% according to EPO 0 076 075. Similarly, epoxide of the formula (V) could be obtained by a yield of 90% by reacting 3-bromo-4-hydroxy-derivative of the formula (IV) with sodium-hydroxide in the presence of a solvent mixture of dioxane and water that is the conversion of (III).fwdarw.(IV).fwdarw.(V) could be reproduced. PA1 The preparation of the end-product of the formula (VI) was carried out by a way which seemed to be the most simple method, that is epoxide of the formula (V) was reacted with 3-pyrrolidone in the presence of sodium-hydride and dimethyl-sulfoxide. As to our surprise a rather complex reaction mixture was obtained and by thin layer chromatography 6-8 components could be detected the amount of which was commeasurable. The reaction was repeated several times, and the end-product of the formula (VI) could be prepared with a yield of 20-25% only by the complicated column chromatography as opposed to the yield of 60% in the disclosure. PA1 4-cyano-phenol of the formula (I) reacts unambiguously with isoprene with an almost quantitative yield, PA1 isoprene is an inexpensive, easily available industrial intermediate product, PA1 chromene of the formula (III) can be obtained with unambiguous reactions with a good yield, and thereby purified by crystallization (as opposed to the vacuum distillation disclosed in EPO 0 076 075), PA1 epoxide of the formula (V) can be obtained according to our invention in high purity in a crystalline form, PA1 end-product of the formula (VI) can be obtained under mild reaction conditions (there is no need to use the expensive sodium-hydride and dimethyl-sulfoxide which is dangerous for the environment and which can only be handled with difficulty, PA1 the purification of the product and the working up of the reaction mixture is simple, PA1 the solvents used can be recovered by distillation and can be recycled, PA1 the reaction can be easily handled and their size can be increased, PA1 industrial production does not need special equipment and the reactions can be carried out in conventional industrial equipment.
According to the procedure disclosed in the EPO 0 076 075 the end-product of the formula (VI) could be prepared only by a yield of 22-26% related to 4-cyano-phenol of the formula (I) and the procedure when reproduced by our own experiments could be carried out with a yield of only 6-8%.
Accordingly, the procedures disclosed in EPO 0 076 075 are not suitable for the industrial preparation of Kromakalim of the formula (VI).